{"gene":"PF3D7_1247400","run_date":"2026-09-08T14:19:06","timeline":{"discoveries":[{"year":2005,"finding":"Recombinant FKBP35 from P. falciparum exhibits PPIase activity and protein-folding (chaperone) activity in vitro; both activities are inhibited by ascomycin and rapamycin but not by cyclosporin A, confirming membership in the FKBP family.","method":"Recombinant protein expression in bacteria; in vitro PPIase activity assay; in vitro chaperone/protein-folding assay; drug inhibition studies","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted enzymatic activities in vitro with defined substrates, replicated independently in two concurrent papers (PMID:15850699 and PMID:15664653)","pmids":["15850699","15664653"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"FKBP35 inhibits purified P. falciparum calcineurin (protein phosphatase 2B) phosphatase activity in the absence of FK506, demonstrating a drug-independent calcineurin-inhibitory activity.","method":"In vitro phosphatase activity assay using purified plasmodial calcineurin and recombinant FKBP35","journal":"Molecular and biochemical parasitology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay replicated independently in two concurrent papers (PMID:15850699 and PMID:15664653)","pmids":["15850699","15664653"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"FKBP35 undergoes stage-specific nucleocytoplasmic shuttling in P. falciparum but does not co-localize with calcineurin inside the parasite cell.","method":"Subcellular localization by immunofluorescence/co-localization microscopy across intra-erythrocytic stages","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct localization experiment, single lab, single paper","pmids":["15850699"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"FKBP35 associates with P. falciparum Hsp90 via its TPR domain; geldanamycin (Hsp90 inhibitor) and ascomycin synergistically inhibit P. falciparum growth.","method":"Co-association/interaction assay (reported as association); drug synergy growth assay in culture","journal":"Molecular and biochemical parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — interaction reported with domain-level mapping, supported by functional synergy data; replicated structurally in later work (PMID:19691130)","pmids":["15850699"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"finding":"FK520 and non-immunosuppressive FK520 analogues inhibit both the PPIase and chaperone activities of recombinant PfFKBP35 in vitro and inhibit parasite growth; compounds that do not inhibit PPIase activity still inhibit chaperone activity, suggesting the antimalarial effect may be mediated via chaperone inhibition rather than PPIase inhibition.","method":"In vitro PPIase activity assay; in vitro chaperone activity assay; P. falciparum culture growth inhibition assay","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic and chaperone assays with multiple structurally distinct compounds, single lab","pmids":["15776382"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2006,"finding":"Full-length PfFKBP35 inhibits calcineurin phosphatase activity basally; the presence of FK506 greatly enhances this calcineurin-inhibitory activity. The FKBD binds FK506 with high affinity as shown by NMR.","method":"In vitro phosphatase activity assay; NMR ligand-binding studies","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay plus NMR binding confirmation, single lab, two orthogonal methods","pmids":["17289400"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Crystal structure of the FK506-binding domain of PfFKBP35 in complex with FK506 at 2.35 Å resolution reveals structural differences in the β5–β6 segment and identifies Cys-106 and Ser-109 (substituting His-87 and Ile-90 in human FKBP12) near the FK506 binding site; NMR shows conformational changes in aromatic residues shaping the binding pocket upon ligand binding.","method":"X-ray crystallography at 2.35 Å; NMR spectroscopy","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR confirmation of conformational changes in a single rigorous study","pmids":["18465874"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"finding":"Solution NMR structure of the FK506-binding domain of PfFKBP35 was determined, providing structural characterization of the isolated FKBD in solution.","method":"NMR spectroscopy (solution structure determination)","journal":"Proteins","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — NMR structure determination, single paper with limited functional follow-up described in the abstract","pmids":["17876830"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"finding":"Crystal structure of the TPR domain of PfFKBP35 was determined; it interacts directly with the Hsp90 C-terminal pentapeptide MEEVD. Surface plasmon resonance and NMR binding studies confirmed this interaction. Mutagenesis of positively charged clamp residues critical for carboxylate-clamping of Hsp90 abolished Hsp90 binding, identifying specific residues essential for the interaction.","method":"X-ray crystallography; surface plasmon resonance; NMR binding studies; site-directed mutagenesis","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus SPR plus NMR plus mutagenesis, multiple orthogonal methods in one rigorous study","pmids":["19691130"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2010,"finding":"The FK506-binding domain of P. vivax FKBP35 (PvFKBP35) was structurally determined by NMR (apo form) and X-ray crystallography (FK506 complex); it exhibits a canonical FKBD fold and shares kinetic PPIase profiles similar to those of PfFKBP35, with differences in ligand-binding mode relative to human FKBP12.","method":"NMR spectroscopy (apo structure); X-ray crystallography (FK506 complex); PPIase kinetic assays","journal":"Protein science : a publication of the Protein Society","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure plus crystal structure plus enzymatic kinetics, multiple orthogonal methods","pmids":["20572013"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""}]},{"year":2013,"finding":"Crystal structures of the FK506-binding domains of PfFKBP35 and PvFKBP35 in complex with the novel small-molecule inhibitor D44 were determined; D44 modulates the PPIase activity of FKBP35 and inhibits P. falciparum growth in a stage-specific manner.","method":"X-ray crystallography; in vitro PPIase activity assay; P. falciparum growth inhibition assay (stage-specific)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus enzymatic assay plus cell-based growth inhibition, multiple orthogonal methods","pmids":["23974147"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""},{"species":"Plasmodium vivax","strain":""}]},{"year":2013,"finding":"Crystal structure of PvFKBP35 FKBD in complex with tetrapeptide substrate sALPFp at 1.65 Å reveals substrate binds in cis conformation; NMR chemical shift perturbations identify D55, H67, V73, and I74 as contact residues; mutagenesis identifies Y100 as a key catalytic residue for PPIase activity.","method":"X-ray crystallography at 1.4 Å (apo) and 1.65 Å (substrate complex); NMR chemical shift perturbation; site-directed mutagenesis with PPIase activity assay","journal":"Eukaryotic cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis with functional readout, multiple orthogonal methods in one study","pmids":["23435727"],"is_preprint":false,"attribution":[{"species":"Plasmodium vivax","strain":""}]},{"year":2013,"finding":"Adamantyl derivatives (SRA/4a and analogues) inhibit PfFKBP35 FKBD PPIase activity at submicromolar concentrations and inhibit P. falciparum 3D7 growth in a stage-specific manner, with activity concentrated at the trophozoite stage; crystal structure of PvFKBD35 in complex with SRA provides structural basis for selective inhibition.","method":"In vitro PPIase inhibition assay; P. falciparum culture growth inhibition; X-ray crystallography of PvFKBD35-SRA complex","journal":"ACS medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus enzymatic assay plus cell-based assay, multiple orthogonal methods","pmids":["24900611"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"},{"species":"Plasmodium vivax","strain":""}]},{"year":2015,"finding":"PfFKBP35 interacts with parasite histones in P. falciparum, as identified by co-immunoprecipitation and yeast two-hybrid screening, suggesting a possible role in modulating gene expression.","method":"Co-immunoprecipitation; yeast two-hybrid screening","journal":"Parasitology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — two orthogonal interaction methods (Co-IP and Y2H), single lab, no further mechanistic follow-up described","pmids":["26156578"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"finding":"Two crystal structures of rapamycin in complex with the FK506-binding domain of PfFKBP35 (oxidized and reduced forms) reveal the same binding-site residues as FK506, with Cys106 4–5 Å from the bound rapamycin, and structural differences from human FKBP12 in the β4–β6 segment.","method":"X-ray crystallography (two structures of PfFKBD–rapamycin complex)","journal":"Acta crystallographica. Section D, Biological crystallography","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution crystal structures with two crystal forms providing independent validation","pmids":["26057671"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"finding":"FK506 and rapamycin act indistinguishably on P. falciparum in culture (same stage-specificity, killing kinetics, and drug interactions), and PfFKBP35's calcineurin-inhibitory activity is independent of FK506 under a range of conditions, making it unlikely that calcineurin inhibition is the mechanism of FK506 antimalarial action; the findings support FKBP35 itself as the relevant antimalarial target.","method":"P. falciparum culture growth/stage-specificity assays; drug interaction experiments; in vitro calcineurin phosphatase assay under varied conditions","journal":"Parasitology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal in vitro and cell-based methods, single lab, mechanistic conclusion supported by convergent evidence","pmids":["28274284"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"finding":"In P. knowlesi, FKBP35 PPIase activity is confined to the FKBD; the TPRD is essential for dimerization; Asp55, Arg60, Trp77 and Phe117 in the FKBD are important for catalysis (significant PPIase activity reduction upon mutation); inhibition of calcineurin requires the FKBD, while the TPRD enhances calcineurin binding efficiency.","method":"Recombinant domain expression; in vitro PPIase activity assay; site-directed mutagenesis; oligomerization analysis; calcineurin phosphatase inhibition assay","journal":"Protein engineering, design & selection : PEDS","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assays plus mutagenesis plus domain-deletion analysis, multiple orthogonal methods","pmids":["31120120"],"is_preprint":false,"attribution":[{"species":"Plasmodium knowlesi","strain":""}]},{"year":2020,"finding":"Targeted covalent inhibitors of PfFKBP35 selectively and covalently modify C106 (adjacent to the rapamycin binding pocket), directly bind FKBP35 in a cellular setting, and exhibit antiplasmodium activity in blood-stage cultured parasites.","method":"Covalent inhibitor synthesis; mass spectrometry-based covalent modification confirmation; cell-based target engagement assay; P. falciparum blood-stage growth inhibition assay","journal":"ACS medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct covalent modification of C106 confirmed by MS plus cellular target engagement plus growth inhibition, multiple orthogonal methods","pmids":["33209191"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"finding":"Genetic depletion of PfFKBP35 is lethal to P. falciparum and produces a delayed death-like phenotype characterized by defective ribosome homeostasis and stalled protein synthesis, establishing FKBP35 as essential for parasite viability. Furthermore, cellular thermal shift assays suggest FK506 exerts its antiproliferative activity in a PfFKBP35-independent manner, identifying putative FK506 targets beyond PfFKBP35.","method":"Conditional knockdown/depletion (genetic validation); cellular thermal shift assay (CETSA); ribosome/translation assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional genetic depletion with defined phenotype plus CETSA target-engagement assay, peer-reviewed, multiple orthogonal methods","pmids":["37934560"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"finding":"In P. knowlesi, FL-FKBP35 binds the Hsp90 C-terminal MEEVD pentapeptide via its TPRD (KD ~55 µM by SPR); the FKBD alone shows no detectable MEEVD binding; MEEVD binding does not significantly affect PPIase activity. A calmodulin-binding motif deletion variant (del-CBM) retains PPIase activity comparable to full-length.","method":"Surface plasmon resonance; in vitro PPIase activity assay; circular dichroism; recombinant domain expression","journal":"Data in brief","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — SPR binding assay plus enzymatic assay, single lab, data paper without extensive functional follow-up","pmids":["42376286"],"is_preprint":false,"attribution":[{"species":"Plasmodium knowlesi","strain":""}]}],"current_model":"PfFKBP35 (PF3D7_1247400) is an essential P. falciparum chaperone-immunophilin whose FKBD catalyzes peptidyl-prolyl cis-trans isomerization (inhibitable by FK506, rapamycin, and ascomycin but not cyclosporin A), whose TPR domain mediates dimerization and direct binding to the Hsp90 C-terminal MEEVD motif via conserved carboxylate-clamp residues, and which inhibits calcineurin phosphatase activity independently of FK506 (though FK506 enhances this inhibition); genetic depletion of FKBP35 is lethal and causes defective ribosome homeostasis and stalled protein synthesis, while interaction with parasite histones suggests an additional role in gene regulation; crystal structures of its FKBD in complex with FK506, rapamycin, and small-molecule inhibitors have defined C106 as a unique cysteine near the drug-binding pocket enabling selective covalent targeting, and cellular thermal shift data indicate that FK506's antiproliferative activity in the parasite operates largely through targets beyond FKBP35 itself."},"narrative":{"mechanistic_narrative":"FKBP35 (PF3D7_1247400) is an essential Plasmodium chaperone-immunophilin that couples peptidyl-prolyl cis-trans isomerase activity to protein-folding and regulatory functions required for parasite viability [PMID:15850699, PMID:15664653, PMID:37934560]. Recombinant P. falciparum FKBP35 possesses both PPIase and chaperone (protein-folding) activities that are inhibited by ascomycin and rapamycin but not by cyclosporin A, placing it firmly in the FKBP family [PMID:15850699, PMID:15664653]. The protein is bipartite: an FK506-binding domain (FKBD) that carries the catalytic PPIase machinery and binds FK506, rapamycin, and small-molecule inhibitors with high affinity [PMID:17289400, PMID:18465874, PMID:26057671], and a tetratricopeptide-repeat (TPR) domain that mediates dimerization and directly engages the Hsp90 C-terminal MEEVD pentapeptide through carboxylate-clamp residues [PMID:19691130]. FKBP35 also inhibits parasite calcineurin phosphatase activity basally, an effect that is FK506-independent but enhanced by FK506 and that requires the FKBD, with the TPR domain augmenting calcineurin binding [PMID:15850699, PMID:15664653, PMID:17289400, PMID:31120120]. Genetic depletion of FKBP35 is lethal and produces a delayed-death-like phenotype of defective ribosome homeostasis and stalled protein synthesis, defining its cellular role in translational/proteostatic homeostasis [PMID:37934560]. Crystallographic and NMR analyses of the FKBD identify Cys106 as a non-canonical residue adjacent to the drug-binding pocket that enables selective covalent inhibitor targeting, supporting FKBP35 as an antimalarial target [PMID:18465874, PMID:26057671, PMID:33209191], although cellular thermal shift data indicate that FK506's antiproliferative activity operates largely through targets beyond FKBP35 itself [PMID:37934560].","teleology":[{"year":2005,"claim":"Establishing that the P. falciparum gene product is a bona fide FKBP-family enzyme was the necessary first step, distinguishing it functionally from cyclophilins and defining its drug sensitivity profile.","evidence":"Recombinant protein PPIase and chaperone assays with FK506-class and cyclosporin drug inhibition, replicated in two concurrent papers","pmids":["15850699","15664653"],"confidence":"High","gaps":["In vitro substrate specificity in the parasite not defined","Physiological folding clients unidentified"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Showing FKBP35 inhibits calcineurin phosphatase without requiring FK506 raised the question of whether the immunophilin regulates a parasite phosphatase pathway directly.","evidence":"In vitro phosphatase assay with purified plasmodial calcineurin and recombinant FKBP35","pmids":["15850699","15664653"],"confidence":"High","gaps":["Whether the FKBP35-calcineurin interaction occurs in vivo not shown","Localization data indicate no co-localization with calcineurin"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Localization and Hsp90-association findings began to place FKBP35 in a chaperone network and cast doubt on a direct calcineurin regulatory role in the cell.","evidence":"Immunofluorescence across intra-erythrocytic stages; TPR-domain association assay; geldanamycin/ascomycin synergy growth assay","pmids":["15850699"],"confidence":"Medium","gaps":["Nucleocytoplasmic shuttling trigger unknown","FKBP35 does not co-localize with calcineurin, leaving the phosphatase inhibition context unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2005,"claim":"Testing FK520 analogues that dissociate PPIase from chaperone inhibition asked which enzymatic activity underlies the antimalarial effect.","evidence":"In vitro PPIase and chaperone assays with multiple structurally distinct compounds plus growth inhibition","pmids":["15776382"],"confidence":"Medium","gaps":["Single lab","Direct in-parasite target engagement not established at this stage"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2008,"claim":"Structural determination of the FKBD in complex with FK506 revealed parasite-specific pocket residues (Cys106, Ser109) that diverge from human FKBP12, opening a route to selective inhibitor design.","evidence":"X-ray crystallography at 2.35 A plus NMR of ligand-induced conformational changes; solution NMR structure of the isolated FKBD","pmids":["18465874","17876830"],"confidence":"High","gaps":["Full-length domain architecture not crystallized","Functional consequence of divergent residues not tested here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2009,"claim":"Structural and biochemical dissection of the TPR domain established the molecular basis for direct Hsp90 recruitment via carboxylate-clamp binding to the MEEVD motif.","evidence":"TPR-domain crystal structure with SPR, NMR binding, and clamp-residue mutagenesis abolishing Hsp90 binding","pmids":["19691130"],"confidence":"High","gaps":["Functional consequence of Hsp90 binding for chaperone clients not defined","Stoichiometry of the FKBP35-Hsp90 assembly unresolved"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2013,"claim":"Substrate-bound and inhibitor-bound FKBD structures in Plasmodium orthologs pinned down catalytic contact residues and demonstrated that PPIase-targeting chemotypes arrest parasite growth stage-specifically.","evidence":"X-ray structures of PvFKBP35 with tetrapeptide substrate and of Pf/Pv FKBD with D44 and adamantyl inhibitors; PPIase assays, mutagenesis (Y100), and stage-specific growth inhibition","pmids":["23435727","23974147","24900611"],"confidence":"High","gaps":["P. vivax catalytic residues inferred to apply to PfFKBP35 by homology, not directly tested in Pf","Endogenous substrate identity unknown"],"attribution":[{"species":"Plasmodium vivax","strain":""},{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2015,"claim":"Identification of histones as FKBP35 interactors introduced a candidate nuclear/gene-regulatory function consistent with its stage-specific nuclear shuttling.","evidence":"Co-immunoprecipitation and yeast two-hybrid screening in P. falciparum","pmids":["26156578"],"confidence":"Medium","gaps":["No functional readout linking FKBP35 to gene expression","Specific histone(s) and modification context not defined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2015,"claim":"Rapamycin-bound FKBD structures confirmed a shared binding site with FK506 and positioned Cys106 within reach of bound ligand, reinforcing the covalent-targeting hypothesis.","evidence":"Two crystal structures (oxidized and reduced) of PfFKBD-rapamycin complex","pmids":["26057671"],"confidence":"High","gaps":["Reactivity of Cys106 not directly demonstrated in this study","Selectivity over human FKBPs not quantified here"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2017,"claim":"Comparing FK506 and rapamycin action and re-examining calcineurin inhibition argued against calcineurin as the antimalarial mechanism and refocused attention on FKBP35 itself as the target.","evidence":"P. falciparum stage-specificity and drug-interaction assays plus calcineurin phosphatase assays under varied conditions","pmids":["28274284"],"confidence":"Medium","gaps":["Single lab","Did not genetically prove FKBP35 dependence"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2018,"claim":"Domain-deletion and mutagenesis analysis in P. knowlesi partitioned FKBP35 functions: FKBD carries catalysis and calcineurin inhibition, while the TPRD drives dimerization and enhances calcineurin binding.","evidence":"Recombinant domain expression, PPIase assays, mutagenesis of catalytic residues, oligomerization analysis, and calcineurin inhibition assays in P. knowlesi","pmids":["31120120"],"confidence":"High","gaps":["P. knowlesi assignments not directly reproduced in PfFKBP35","In-cell relevance of dimerization not tested"],"attribution":[{"species":"Plasmodium knowlesi","strain":""}]},{"year":2020,"claim":"Targeted covalent inhibitors demonstrated that Cys106 can be selectively modified and that FKBP35 is engaged in living blood-stage parasites, validating the covalent chemistry predicted by the structures.","evidence":"Covalent inhibitor synthesis, mass spectrometry of C106 modification, cellular target engagement, and blood-stage growth inhibition","pmids":["33209191"],"confidence":"High","gaps":["On-target contribution to killing not fully separated from off-target effects","Downstream consequences of FKBD inhibition not mapped"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2023,"claim":"Conditional genetic depletion resolved the essentiality question and revealed the cellular process FKBP35 supports, while CETSA reframed FK506's mechanism as largely FKBP35-independent.","evidence":"Conditional knockdown with delayed-death phenotyping, ribosome/translation assays, and cellular thermal shift assay in P. falciparum","pmids":["37934560"],"confidence":"High","gaps":["Molecular link between FKBP35 and ribosome homeostasis unresolved","Identity of FK506 targets beyond FKBP35 not determined"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2026,"claim":"Quantitative binding analysis in P. knowlesi confirmed TPRD-exclusive MEEVD engagement and showed Hsp90 binding does not alter PPIase activity, clarifying functional independence of the two domains.","evidence":"SPR MEEVD binding (KD ~55 uM), PPIase assays, CD, and domain/CBM-deletion variants in P. knowlesi","pmids":["42376286"],"confidence":"Medium","gaps":["Data paper without extensive functional follow-up","Function of the calmodulin-binding motif not established"],"attribution":[{"species":"Plasmodium knowlesi","strain":""}]},{"year":null,"claim":"The endogenous PPIase/chaperone substrates of FKBP35 and the molecular basis for its requirement in ribosome homeostasis and protein synthesis remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No physiological folding client identified","Mechanistic link between FKBP35 loss and stalled translation not established","Functional significance of histone interaction and nuclear shuttling unresolved"],"attribution":[]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":["FKBP35-Hsp90 (via TPR domain-MEEVD interaction)","FKBP35 homodimer (TPR domain-mediated)"],"partners":["HSP90 (C-TERMINAL MEEVD PENTAPEPTIDE)","CALCINEURIN (PROTEIN PHOSPHATASE 2B)","PARASITE HISTONES"],"other_free_text":["Bipartite architecture: FKBD (catalysis, drug binding, calcineurin inhibition) and TPRD (dimerization, Hsp90 MEEVD binding, enhanced calcineurin binding)","Drug sensitivity: inhibited by FK506, rapamycin, ascomycin/FK520; not by cyclosporin A","Cys106 is a non-canonical FKBD pocket residue enabling selective covalent inhibitor targeting","Essential gene; genetic depletion causes delayed-death-like phenotype with defective ribosome homeostasis and stalled protein synthesis","CETSA indicates FK506 antiproliferative activity is largely FKBP35-independent","Structural/biochemical work in P. vivax and P. knowlesi orthologs used to infer PfFKBP35 catalytic and domain properties"]}},"prefetch_data":{},"corpus_meta":[{"pmid":"15850699","id":"PMC_15850699","title":"The FK506-binding protein of the malaria parasite, Plasmodium falciparum, is a FK506-sensitive chaperone with FK506-independent calcineurin-inhibitory activity.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15850699","citation_count":56,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FKBP35","PfFKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15664653","id":"PMC_15664653","title":"A Plasmodium falciparum FK506-binding protein (FKBP) with peptidyl-prolyl cis-trans isomerase and chaperone activities.","date":"2005","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/15664653","citation_count":51,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfFKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"15776382","id":"PMC_15776382","title":"Antimalarial effects of macrolactones related to FK520 (ascomycin) are independent of the immunosuppressive properties of the compounds.","date":"2005","source":"The Journal of infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/15776382","citation_count":31,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfFKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"18465874","id":"PMC_18465874","title":"Crystal structure of the FK506 binding domain of Plasmodium falciparum FKBP35 in complex with FK506.","date":"2008","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18465874","citation_count":27,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"23974147","id":"PMC_23974147","title":"Small molecule Plasmodium FKBP35 inhibitor as a potential antimalaria agent.","date":"2013","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/23974147","citation_count":26,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FKBP35","PfFKBP35","PvFKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"20572013","id":"PMC_20572013","title":"NMR and crystallographic structures of the FK506 binding domain of human malarial parasite Plasmodium vivax FKBP35.","date":"2010","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/20572013","citation_count":24,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FKBP35","PfFKBP35","PvFKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"19691130","id":"PMC_19691130","title":"Crystallographic structure of the tetratricopeptide repeat domain of Plasmodium falciparum FKBP35 and its molecular interaction with Hsp90 C-terminal pentapeptide.","date":"2009","source":"Protein science : a publication of the Protein Society","url":"https://pubmed.ncbi.nlm.nih.gov/19691130","citation_count":23,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["FKBP35","PfFKBP35"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"24560171","id":"PMC_24560171","title":"Co-chaperones of Hsp90 in Plasmodium falciparum and their concerted roles in cellular 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confirming membership in the FKBP family.\",\n      \"method\": \"Recombinant protein expression in bacteria; in vitro PPIase activity assay; in vitro chaperone/protein-folding assay; drug inhibition studies\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted enzymatic activities in vitro with defined substrates, replicated independently in two concurrent papers (PMID:15850699 and PMID:15664653)\",\n      \"pmids\": [\"15850699\", \"15664653\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP35 inhibits purified P. falciparum calcineurin (protein phosphatase 2B) phosphatase activity in the absence of FK506, demonstrating a drug-independent calcineurin-inhibitory activity.\",\n      \"method\": \"In vitro phosphatase activity assay using purified plasmodial calcineurin and recombinant FKBP35\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay replicated independently in two concurrent papers (PMID:15850699 and PMID:15664653)\",\n      \"pmids\": [\"15850699\", \"15664653\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP35 undergoes stage-specific nucleocytoplasmic shuttling in P. falciparum but does not co-localize with calcineurin inside the parasite cell.\",\n      \"method\": \"Subcellular localization by immunofluorescence/co-localization microscopy across intra-erythrocytic stages\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct localization experiment, single lab, single paper\",\n      \"pmids\": [\"15850699\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FKBP35 associates with P. falciparum Hsp90 via its TPR domain; geldanamycin (Hsp90 inhibitor) and ascomycin synergistically inhibit P. falciparum growth.\",\n      \"method\": \"Co-association/interaction assay (reported as association); drug synergy growth assay in culture\",\n      \"journal\": \"Molecular and biochemical parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — interaction reported with domain-level mapping, supported by functional synergy data; replicated structurally in later work (PMID:19691130)\",\n      \"pmids\": [\"15850699\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"FK520 and non-immunosuppressive FK520 analogues inhibit both the PPIase and chaperone activities of recombinant PfFKBP35 in vitro and inhibit parasite growth; compounds that do not inhibit PPIase activity still inhibit chaperone activity, suggesting the antimalarial effect may be mediated via chaperone inhibition rather than PPIase inhibition.\",\n      \"method\": \"In vitro PPIase activity assay; in vitro chaperone activity assay; P. falciparum culture growth inhibition assay\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic and chaperone assays with multiple structurally distinct compounds, single lab\",\n      \"pmids\": [\"15776382\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Full-length PfFKBP35 inhibits calcineurin phosphatase activity basally; the presence of FK506 greatly enhances this calcineurin-inhibitory activity. The FKBD binds FK506 with high affinity as shown by NMR.\",\n      \"method\": \"In vitro phosphatase activity assay; NMR ligand-binding studies\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay plus NMR binding confirmation, single lab, two orthogonal methods\",\n      \"pmids\": [\"17289400\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Crystal structure of the FK506-binding domain of PfFKBP35 in complex with FK506 at 2.35 Å resolution reveals structural differences in the β5–β6 segment and identifies Cys-106 and Ser-109 (substituting His-87 and Ile-90 in human FKBP12) near the FK506 binding site; NMR shows conformational changes in aromatic residues shaping the binding pocket upon ligand binding.\",\n      \"method\": \"X-ray crystallography at 2.35 Å; NMR spectroscopy\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR confirmation of conformational changes in a single rigorous study\",\n      \"pmids\": [\"18465874\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Solution NMR structure of the FK506-binding domain of PfFKBP35 was determined, providing structural characterization of the isolated FKBD in solution.\",\n      \"method\": \"NMR spectroscopy (solution structure determination)\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — NMR structure determination, single paper with limited functional follow-up described in the abstract\",\n      \"pmids\": [\"17876830\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Crystal structure of the TPR domain of PfFKBP35 was determined; it interacts directly with the Hsp90 C-terminal pentapeptide MEEVD. Surface plasmon resonance and NMR binding studies confirmed this interaction. Mutagenesis of positively charged clamp residues critical for carboxylate-clamping of Hsp90 abolished Hsp90 binding, identifying specific residues essential for the interaction.\",\n      \"method\": \"X-ray crystallography; surface plasmon resonance; NMR binding studies; site-directed mutagenesis\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus SPR plus NMR plus mutagenesis, multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"19691130\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The FK506-binding domain of P. vivax FKBP35 (PvFKBP35) was structurally determined by NMR (apo form) and X-ray crystallography (FK506 complex); it exhibits a canonical FKBD fold and shares kinetic PPIase profiles similar to those of PfFKBP35, with differences in ligand-binding mode relative to human FKBP12.\",\n      \"method\": \"NMR spectroscopy (apo structure); X-ray crystallography (FK506 complex); PPIase kinetic assays\",\n      \"journal\": \"Protein science : a publication of the Protein Society\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure plus crystal structure plus enzymatic kinetics, multiple orthogonal methods\",\n      \"pmids\": [\"20572013\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the FK506-binding domains of PfFKBP35 and PvFKBP35 in complex with the novel small-molecule inhibitor D44 were determined; D44 modulates the PPIase activity of FKBP35 and inhibits P. falciparum growth in a stage-specific manner.\",\n      \"method\": \"X-ray crystallography; in vitro PPIase activity assay; P. falciparum growth inhibition assay (stage-specific)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus enzymatic assay plus cell-based growth inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"23974147\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"\"},\n        {\"species\": \"Plasmodium vivax\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of PvFKBP35 FKBD in complex with tetrapeptide substrate sALPFp at 1.65 Å reveals substrate binds in cis conformation; NMR chemical shift perturbations identify D55, H67, V73, and I74 as contact residues; mutagenesis identifies Y100 as a key catalytic residue for PPIase activity.\",\n      \"method\": \"X-ray crystallography at 1.4 Å (apo) and 1.65 Å (substrate complex); NMR chemical shift perturbation; site-directed mutagenesis with PPIase activity assay\",\n      \"journal\": \"Eukaryotic cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus NMR plus mutagenesis with functional readout, multiple orthogonal methods in one study\",\n      \"pmids\": [\"23435727\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Adamantyl derivatives (SRA/4a and analogues) inhibit PfFKBP35 FKBD PPIase activity at submicromolar concentrations and inhibit P. falciparum 3D7 growth in a stage-specific manner, with activity concentrated at the trophozoite stage; crystal structure of PvFKBD35 in complex with SRA provides structural basis for selective inhibition.\",\n      \"method\": \"In vitro PPIase inhibition assay; P. falciparum culture growth inhibition; X-ray crystallography of PvFKBD35-SRA complex\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus enzymatic assay plus cell-based assay, multiple orthogonal methods\",\n      \"pmids\": [\"24900611\"],\n      \"is_preprint\": false,\n      \"attribution\": [\n        {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"},\n        {\"species\": \"Plasmodium vivax\", \"strain\": \"\"}\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PfFKBP35 interacts with parasite histones in P. falciparum, as identified by co-immunoprecipitation and yeast two-hybrid screening, suggesting a possible role in modulating gene expression.\",\n      \"method\": \"Co-immunoprecipitation; yeast two-hybrid screening\",\n      \"journal\": \"Parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — two orthogonal interaction methods (Co-IP and Y2H), single lab, no further mechanistic follow-up described\",\n      \"pmids\": [\"26156578\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Two crystal structures of rapamycin in complex with the FK506-binding domain of PfFKBP35 (oxidized and reduced forms) reveal the same binding-site residues as FK506, with Cys106 4–5 Å from the bound rapamycin, and structural differences from human FKBP12 in the β4–β6 segment.\",\n      \"method\": \"X-ray crystallography (two structures of PfFKBD–rapamycin complex)\",\n      \"journal\": \"Acta crystallographica. Section D, Biological crystallography\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution crystal structures with two crystal forms providing independent validation\",\n      \"pmids\": [\"26057671\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FK506 and rapamycin act indistinguishably on P. falciparum in culture (same stage-specificity, killing kinetics, and drug interactions), and PfFKBP35's calcineurin-inhibitory activity is independent of FK506 under a range of conditions, making it unlikely that calcineurin inhibition is the mechanism of FK506 antimalarial action; the findings support FKBP35 itself as the relevant antimalarial target.\",\n      \"method\": \"P. falciparum culture growth/stage-specificity assays; drug interaction experiments; in vitro calcineurin phosphatase assay under varied conditions\",\n      \"journal\": \"Parasitology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal in vitro and cell-based methods, single lab, mechanistic conclusion supported by convergent evidence\",\n      \"pmids\": [\"28274284\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In P. knowlesi, FKBP35 PPIase activity is confined to the FKBD; the TPRD is essential for dimerization; Asp55, Arg60, Trp77 and Phe117 in the FKBD are important for catalysis (significant PPIase activity reduction upon mutation); inhibition of calcineurin requires the FKBD, while the TPRD enhances calcineurin binding efficiency.\",\n      \"method\": \"Recombinant domain expression; in vitro PPIase activity assay; site-directed mutagenesis; oligomerization analysis; calcineurin phosphatase inhibition assay\",\n      \"journal\": \"Protein engineering, design & selection : PEDS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assays plus mutagenesis plus domain-deletion analysis, multiple orthogonal methods\",\n      \"pmids\": [\"31120120\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Targeted covalent inhibitors of PfFKBP35 selectively and covalently modify C106 (adjacent to the rapamycin binding pocket), directly bind FKBP35 in a cellular setting, and exhibit antiplasmodium activity in blood-stage cultured parasites.\",\n      \"method\": \"Covalent inhibitor synthesis; mass spectrometry-based covalent modification confirmation; cell-based target engagement assay; P. falciparum blood-stage growth inhibition assay\",\n      \"journal\": \"ACS medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct covalent modification of C106 confirmed by MS plus cellular target engagement plus growth inhibition, multiple orthogonal methods\",\n      \"pmids\": [\"33209191\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genetic depletion of PfFKBP35 is lethal to P. falciparum and produces a delayed death-like phenotype characterized by defective ribosome homeostasis and stalled protein synthesis, establishing FKBP35 as essential for parasite viability. Furthermore, cellular thermal shift assays suggest FK506 exerts its antiproliferative activity in a PfFKBP35-independent manner, identifying putative FK506 targets beyond PfFKBP35.\",\n      \"method\": \"Conditional knockdown/depletion (genetic validation); cellular thermal shift assay (CETSA); ribosome/translation assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional genetic depletion with defined phenotype plus CETSA target-engagement assay, peer-reviewed, multiple orthogonal methods\",\n      \"pmids\": [\"37934560\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In P. knowlesi, FL-FKBP35 binds the Hsp90 C-terminal MEEVD pentapeptide via its TPRD (KD ~55 µM by SPR); the FKBD alone shows no detectable MEEVD binding; MEEVD binding does not significantly affect PPIase activity. A calmodulin-binding motif deletion variant (del-CBM) retains PPIase activity comparable to full-length.\",\n      \"method\": \"Surface plasmon resonance; in vitro PPIase activity assay; circular dichroism; recombinant domain expression\",\n      \"journal\": \"Data in brief\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — SPR binding assay plus enzymatic assay, single lab, data paper without extensive functional follow-up\",\n      \"pmids\": [\"42376286\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"PfFKBP35 (PF3D7_1247400) is an essential P. falciparum chaperone-immunophilin whose FKBD catalyzes peptidyl-prolyl cis-trans isomerization (inhibitable by FK506, rapamycin, and ascomycin but not cyclosporin A), whose TPR domain mediates dimerization and direct binding to the Hsp90 C-terminal MEEVD motif via conserved carboxylate-clamp residues, and which inhibits calcineurin phosphatase activity independently of FK506 (though FK506 enhances this inhibition); genetic depletion of FKBP35 is lethal and causes defective ribosome homeostasis and stalled protein synthesis, while interaction with parasite histones suggests an additional role in gene regulation; crystal structures of its FKBD in complex with FK506, rapamycin, and small-molecule inhibitors have defined C106 as a unique cysteine near the drug-binding pocket enabling selective covalent targeting, and cellular thermal shift data indicate that FK506's antiproliferative activity in the parasite operates largely through targets beyond FKBP35 itself.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FKBP35 (PF3D7_1247400) is an essential Plasmodium chaperone-immunophilin that couples peptidyl-prolyl cis-trans isomerase activity to protein-folding and regulatory functions required for parasite viability [#0, #18]. Recombinant P. falciparum FKBP35 possesses both PPIase and chaperone (protein-folding) activities that are inhibited by ascomycin and rapamycin but not by cyclosporin A, placing it firmly in the FKBP family [#0]. The protein is bipartite: an FK506-binding domain (FKBD) that carries the catalytic PPIase machinery and binds FK506, rapamycin, and small-molecule inhibitors with high affinity [#5, #6, #14], and a tetratricopeptide-repeat (TPR) domain that mediates dimerization and directly engages the Hsp90 C-terminal MEEVD pentapeptide through carboxylate-clamp residues [#8]. FKBP35 also inhibits parasite calcineurin phosphatase activity basally, an effect that is FK506-independent but enhanced by FK506 and that requires the FKBD, with the TPR domain augmenting calcineurin binding [#1, #5, #16]. Genetic depletion of FKBP35 is lethal and produces a delayed-death-like phenotype of defective ribosome homeostasis and stalled protein synthesis, defining its cellular role in translational/proteostatic homeostasis [#18]. Crystallographic and NMR analyses of the FKBD identify Cys106 as a non-canonical residue adjacent to the drug-binding pocket that enables selective covalent inhibitor targeting, supporting FKBP35 as an antimalarial target [#6, #14, #17], although cellular thermal shift data indicate that FK506's antiproliferative activity operates largely through targets beyond FKBP35 itself [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Establishing that the P. falciparum gene product is a bona fide FKBP-family enzyme was the necessary first step, distinguishing it functionally from cyclophilins and defining its drug sensitivity profile.\",\n      \"evidence\": \"Recombinant protein PPIase and chaperone assays with FK506-class and cyclosporin drug inhibition, replicated in two concurrent papers\",\n      \"pmids\": [\"15850699\", \"15664653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro substrate specificity in the parasite not defined\", \"Physiological folding clients unidentified\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showing FKBP35 inhibits calcineurin phosphatase without requiring FK506 raised the question of whether the immunophilin regulates a parasite phosphatase pathway directly.\",\n      \"evidence\": \"In vitro phosphatase assay with purified plasmodial calcineurin and recombinant FKBP35\",\n      \"pmids\": [\"15850699\", \"15664653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the FKBP35-calcineurin interaction occurs in vivo not shown\", \"Localization data indicate no co-localization with calcineurin\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Localization and Hsp90-association findings began to place FKBP35 in a chaperone network and cast doubt on a direct calcineurin regulatory role in the cell.\",\n      \"evidence\": \"Immunofluorescence across intra-erythrocytic stages; TPR-domain association assay; geldanamycin/ascomycin synergy growth assay\",\n      \"pmids\": [\"15850699\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nucleocytoplasmic shuttling trigger unknown\", \"FKBP35 does not co-localize with calcineurin, leaving the phosphatase inhibition context unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Testing FK520 analogues that dissociate PPIase from chaperone inhibition asked which enzymatic activity underlies the antimalarial effect.\",\n      \"evidence\": \"In vitro PPIase and chaperone assays with multiple structurally distinct compounds plus growth inhibition\",\n      \"pmids\": [\"15776382\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct in-parasite target engagement not established at this stage\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Structural determination of the FKBD in complex with FK506 revealed parasite-specific pocket residues (Cys106, Ser109) that diverge from human FKBP12, opening a route to selective inhibitor design.\",\n      \"evidence\": \"X-ray crystallography at 2.35 A plus NMR of ligand-induced conformational changes; solution NMR structure of the isolated FKBD\",\n      \"pmids\": [\"18465874\", \"17876830\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length domain architecture not crystallized\", \"Functional consequence of divergent residues not tested here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Structural and biochemical dissection of the TPR domain established the molecular basis for direct Hsp90 recruitment via carboxylate-clamp binding to the MEEVD motif.\",\n      \"evidence\": \"TPR-domain crystal structure with SPR, NMR binding, and clamp-residue mutagenesis abolishing Hsp90 binding\",\n      \"pmids\": [\"19691130\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of Hsp90 binding for chaperone clients not defined\", \"Stoichiometry of the FKBP35-Hsp90 assembly unresolved\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Substrate-bound and inhibitor-bound FKBD structures in Plasmodium orthologs pinned down catalytic contact residues and demonstrated that PPIase-targeting chemotypes arrest parasite growth stage-specifically.\",\n      \"evidence\": \"X-ray structures of PvFKBP35 with tetrapeptide substrate and of Pf/Pv FKBD with D44 and adamantyl inhibitors; PPIase assays, mutagenesis (Y100), and stage-specific growth inhibition\",\n      \"pmids\": [\"23435727\", \"23974147\", \"24900611\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"P. vivax catalytic residues inferred to apply to PfFKBP35 by homology, not directly tested in Pf\", \"Endogenous substrate identity unknown\"],\n      \"attribution\": [{\"species\": \"Plasmodium vivax\", \"strain\": \"\"}, {\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of histones as FKBP35 interactors introduced a candidate nuclear/gene-regulatory function consistent with its stage-specific nuclear shuttling.\",\n      \"evidence\": \"Co-immunoprecipitation and yeast two-hybrid screening in P. falciparum\",\n      \"pmids\": [\"26156578\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional readout linking FKBP35 to gene expression\", \"Specific histone(s) and modification context not defined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Rapamycin-bound FKBD structures confirmed a shared binding site with FK506 and positioned Cys106 within reach of bound ligand, reinforcing the covalent-targeting hypothesis.\",\n      \"evidence\": \"Two crystal structures (oxidized and reduced) of PfFKBD-rapamycin complex\",\n      \"pmids\": [\"26057671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reactivity of Cys106 not directly demonstrated in this study\", \"Selectivity over human FKBPs not quantified here\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Comparing FK506 and rapamycin action and re-examining calcineurin inhibition argued against calcineurin as the antimalarial mechanism and refocused attention on FKBP35 itself as the target.\",\n      \"evidence\": \"P. falciparum stage-specificity and drug-interaction assays plus calcineurin phosphatase assays under varied conditions\",\n      \"pmids\": [\"28274284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not genetically prove FKBP35 dependence\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Domain-deletion and mutagenesis analysis in P. knowlesi partitioned FKBP35 functions: FKBD carries catalysis and calcineurin inhibition, while the TPRD drives dimerization and enhances calcineurin binding.\",\n      \"evidence\": \"Recombinant domain expression, PPIase assays, mutagenesis of catalytic residues, oligomerization analysis, and calcineurin inhibition assays in P. knowlesi\",\n      \"pmids\": [\"31120120\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"P. knowlesi assignments not directly reproduced in PfFKBP35\", \"In-cell relevance of dimerization not tested\"],\n      \"attribution\": [{\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Targeted covalent inhibitors demonstrated that Cys106 can be selectively modified and that FKBP35 is engaged in living blood-stage parasites, validating the covalent chemistry predicted by the structures.\",\n      \"evidence\": \"Covalent inhibitor synthesis, mass spectrometry of C106 modification, cellular target engagement, and blood-stage growth inhibition\",\n      \"pmids\": [\"33209191\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"On-target contribution to killing not fully separated from off-target effects\", \"Downstream consequences of FKBD inhibition not mapped\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Conditional genetic depletion resolved the essentiality question and revealed the cellular process FKBP35 supports, while CETSA reframed FK506's mechanism as largely FKBP35-independent.\",\n      \"evidence\": \"Conditional knockdown with delayed-death phenotyping, ribosome/translation assays, and cellular thermal shift assay in P. falciparum\",\n      \"pmids\": [\"37934560\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between FKBP35 and ribosome homeostasis unresolved\", \"Identity of FK506 targets beyond FKBP35 not determined\"],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Quantitative binding analysis in P. knowlesi confirmed TPRD-exclusive MEEVD engagement and showed Hsp90 binding does not alter PPIase activity, clarifying functional independence of the two domains.\",\n      \"evidence\": \"SPR MEEVD binding (KD ~55 uM), PPIase assays, CD, and domain/CBM-deletion variants in P. knowlesi\",\n      \"pmids\": [\"42376286\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Data paper without extensive functional follow-up\", \"Function of the calmodulin-binding motif not established\"],\n      \"attribution\": [{\"species\": \"Plasmodium knowlesi\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous PPIase/chaperone substrates of FKBP35 and the molecular basis for its requirement in ribosome homeostasis and protein synthesis remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No physiological folding client identified\", \"Mechanistic link between FKBP35 loss and stalled translation not established\", \"Functional significance of histone interaction and nuclear shuttling unresolved\"],\n      \"attribution\": []\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003755\", \"supporting_discovery_ids\": [0, 4, 6, 11, 12, 16, 19]},\n      {\"term_id\": \"GO:0051082\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0004864\", \"supporting_discovery_ids\": [1, 5, 16]},\n      {\"term_id\": \"GO:0051879\", \"supporting_discovery_ids\": [3, 8, 19]},\n      {\"term_id\": \"GO:0042803\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005737\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0006457\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0006412\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"complexes\": [\n      \"FKBP35-Hsp90 (via TPR domain-MEEVD interaction)\",\n      \"FKBP35 homodimer (TPR domain-mediated)\"\n    ],\n    \"partners\": [\n      \"Hsp90 (C-terminal MEEVD pentapeptide)\",\n      \"calcineurin (protein phosphatase 2B)\",\n      \"parasite histones\"\n    ],\n    \"other_free_text\": [\n      \"Bipartite architecture: FKBD (catalysis, drug binding, calcineurin inhibition) and TPRD (dimerization, Hsp90 MEEVD binding, enhanced calcineurin binding)\",\n      \"Drug sensitivity: inhibited by FK506, rapamycin, ascomycin/FK520; not by cyclosporin A\",\n      \"Cys106 is a non-canonical FKBD pocket residue enabling selective covalent inhibitor targeting\",\n      \"Essential gene; genetic depletion causes delayed-death-like phenotype with defective ribosome homeostasis and stalled protein synthesis\",\n      \"CETSA indicates FK506 antiproliferative activity is largely FKBP35-independent\",\n      \"Structural/biochemical work in P. vivax and P. knowlesi orthologs used to infer PfFKBP35 catalytic and domain properties\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1247400","name":null,"product":"peptidyl-prolyl cis-trans isomerase FKBP35","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1460400","name":null,"product":"peptidyl-prolyl cis-trans isomerase FKBP35, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1467100","name":null,"product":"peptidyl-prolyl cis-trans isomerase FKBP35","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"FKBP35","evaluation":null}